Cellular uptake of lithium via amino acid transport system A

We now add to the agencies by which cells take up lithium the process of cotransport with neutral amino acids via System A. In the Ehrlich cell various natural and synthetic amino acids, depending on their structure, can cause substantial accelerations of Li⁺ uptake over a considerable range of levels of Na⁺, Li⁺ and H⁺. Half the maximal augmentation of uptake, namely 1.2 mequiv. Li/kg cell water per 15 min, was obtained for 5.4 mM alanine in a double-reciprocal plot. Alanine also stimulated the exodus of Li⁺ from the Ehrlich cell. The human red blood cell, lacking System A as it does, becomes an imperfect model for studying cellular uptake of Li⁺. Until the Li⁺ dependence of amino acid uptake in the reticulocyte is known, reticulocytosis can be suspected of contributing to the interpersonal variations seen in Li⁺-for-Na⁺ exchange.     

Lithium inhibits glycogen synthase kinase-3 activity and mimics Wingless signalling in intact cells

Background Exposing eukaryotic cells to lithium ions (Li⁺) during development has marked effects on cell fate and organization. The phenotypic consequences of Li⁺ treatment on Xenopus embryos and sporulating Dictyostelium are similar to the effects of inhibition or disruption, respectively, of a highly conserved protein serine/threonine kinase, glycogen synthase kinase-3 (GSK-3). In Drosophila, the GSK-3 homologue is encoded by zw3^sgg, a segment-polarity gene involved in embryogenesis that acts downstream of wg. In higher eukaryotes, GSK-3 has been implicated in signal transduction pathways downstream of phosphoinositide 3-kinase and mitogen-activated protein kinases.Results We investigated the effect of Li⁺ on the activity of the GSK-3 family. At physiological doses, Li⁺ inhibits the activity of human GSK-3β and Drosophila Zw3^Sgg, but has no effect on other protein kinases. The effect of Li⁺ on GSK-3 is reversible in vitro. Treatment of cells with Li⁺ inhibits GSK-3-dependent phosphorylation of the microtubule-associated protein Tau. Li⁺ treatment of Drosophila S2 cells and rat PC12 cells induces accumulation of cytoplasmic Armadillo/β-catenin, demonstrating that Li⁺ can mimic Wingless signalling in intact cells, consistent with its inhibition of GSK-3.Conclusions Li⁺ acts as a specific inhibitor of the GSK-3 family of protein kinases in vitro and in intact cells, and mimics Wingless signalling. This reveals a possible molecular mechanism of Li⁺ action on development and differentiation.     

Effects of a Chronic Lithium Treatment on Cortical Serotonin Uptake Sites and 5-HT1A Receptors

The objectives of this study were to characterize the effects of a chronic lithium (Li⁺) treatment on serotonin (5-HT) uptake sites and on 5-HT_1A receptors, and to determine the eventual reversibility of the treatment. The experiments were carried out with membranes from rat cerebral cortex using 8-hydroxy-2-(propylamino)tetralin, or [³H]8-OH-DPAT, and [³H]citalopram to label 5-HT_1A receptors and 5-HT uptake sites, respectively. Endogenous levels of 5-HT and 5-hydroxyindole-3-acetic acid (5-HIAA) were measured by high-performance liquid chromatography in the cingulate cortex. The saturation curves with [³H]8-OH-DPAT were always best fitted a two-site model. After a treatment with Li⁺ for 28 days, no alterations in the binding parameters of [³H]8-OH-DPAT to the high- and low-affinity binding sites could be documented. However, competition curves with 5-HT to inhibit [³H]8-OH-DPAT binding revealed a decreased proportion of sites with high affinity for the agonist, together with an increased density of sites with low affinity for 5-HT, suggesting an alteration in the coupling efficacy between 5-HT_1A receptors and their transduction systems. Saturation studies with [³H]citalopram showed an increase (>40%) in the density of 5-HT uptake sites after chronic Li⁺, suggesting a more efficient 5-HT uptake process for the treated animals, in accord with clinical observations. Although 5-HT contents in cingulate cortex remained unchanged after the treatment, 5-HIAA levels decreased (>30%), leading to a diminished (almost 50%) 5-HT turnover; and also reflecting a more efficient uptake in the treated rats, so that less 5-HT could be degraded by extracellular monoamine oxidase. All the effects revealed by [³H]8-OH-DPAT and [³H]citalopram were reversed following a recovery period of two days without Li⁺. Since symptoms of bipolar affective disorders may reappear if the chronic Li⁺ treatment is interrupted, the reversibility of the observed effects further supports the importance of central 5-HT synaptic transmission in the pathophysiology and treatment of human affective disorders.     

Transport Pathways for Therapeutic Concentrations of Lithium in Rat Liver

Although both amiloride- and phloretin-sensitive Na⁺/Li⁺ exchange activities have been reported in mammalian red blood cells, it is still unclear whether or not the two are mediated by the same pathway. Also, little is known about the relative contribution of these transport mechanisms to the entry of therapeutic concentrations of Li⁺ (0.2–2 mm) into cells other than erythrocytes. Here, we describe characteristics of these transport systems in rat isolated hepatocytes in suspension. Uptake of Li⁺ by hepatocytes, preloaded with Na⁺ and incubated in the presence of ouabain and bumetanide, comprised three components. (a) An amiloride-sensitive component, with apparent K _m 1.2 mm Li⁺, V _max 40 μmol · (kg dry wt · min)⁻¹, showed increased activity at low intracellular pH. The relationship of this component to the concentration of intracellular H⁺ was curvilinear suggesting a modifier role of [H⁺] _i . This system persisted in Na⁺-depleted cells, although with apparent K _m 3.8 mm. (b) A phloretin-sensitive component, with K _m 1.2 mm, V _max 21 μmol · (kg · min)⁻¹, was unaffected by pH but was inactive in Na⁺-depleted cells. Phloretin inhibited Li⁺ uptake and Na⁺ efflux in parallel. (c) A residual uptake increased linearly with the external Li⁺ concentration and represented an increasing proportion of the total uptake. The results strongly suggest that the amiloride-sensitive and the phloretin-sensitive Li⁺ uptake in rat liver are mediated by two separate pathways which can be distinguished by their sensitivity to inhibitors and intracellular [H⁺]. Received: 8 April 1999/Revised: 19 July 1999     

Regional and Subcellular Localization of Li+ and Other Cations in the Rat Brain Following Long-Term Lithium Administration

Abstract: Rats were given LiCl in their diet (40 mmol/kg dry weight) for at least 3 months to elucidate the regional and subcellular localization of Li⁺ in the brain as well as the effect of chronic lithium administration on the distribution of other cations. At steady-state the mean concentrations of Li⁺ were 0.66 mmol/kg wet weight in the whole brain and 0.52 mM in plasma. The tissue/plasma concentration ratio exceeded unity in all anatomical regions. No region showed excessive accumulation of Li⁺. Whole brain or regional contents of Na⁺ or K⁺ were unaffected by lithium treatment. Subcellular Li⁺ localization was demonstrated in nuclear, crude mitochondrial, and microsomal fractions of whole brain homogenate. Subfractionation of the crude mitochondrial fraction revealed energy-independent intrasynaptosomal and intramitochondrial Li⁺ and K⁺ localization at 0–4°C. Li⁺ administered in vivo disappeared within 10 min from synaptosomes incubated at 37°C. Li⁺ added in vitro at 1 mM attained a synaptosomal steady-state concentration within 30 min at 37°C. In control rats, synaptosomal concentrations and synaptosomal/medium concentration gradients of cations paralleled their respective in vivo concentrations and gradients. Lithium treatment caused synaptosomal depletion of K⁺ and Mg²⁺ and hence probably partial membrane depolarization. Addition of 1 mM Li⁺ in vitro also caused synaptosomal Mg²⁺ depletion. The results indicate that Li⁺ is “accumulated” in brain sediments and synaptosomes following its long-term treatment. The estimated intracellular and intrasynaptosomal Li⁺ concentrations are lower than predicted by passive distribution according to the Nernst equation, evidencing active extrusion of Li⁺.     

Preparation of synaptosomes and vesicles with sodium diatrizoate

Abstract— Synaptosomes were prepared from rat brain on a continuous gradient of sodium diatrizoate and compared with synaptosomes obtained on a discontinuous sucrose gradient. The yield of synaptosomal protein using diatrizoate was double that obtained with sucrose. No significant differences in quality between the two preparations were found based on measurement of: β-glucuronidase, RNA polymerase, 2′,3′-cyclic nucleotide 3′-phosphohydrolase, total and Na⁺, K⁺ -ATPase, acetylcholinesterase, lactic acid dehydrogenase, glucose utilization, and serotonin uptake. Electron microscopy showed the vesicles in the diatrizoate synaptosomes to be better preserved. Vesicles prepared on diatrizoate segregated into two distinct bands which differed in electron microscopic appearance and enzyme activity. The less dense vesicles were smaller, had much higher Mg²⁺ -ATPase activity, and a lower content of acetylcholinesterase than the more dense vesicles. The less dense vesicle preparation was very homogeneous morphologically, free of myelin and mitochondria, and contained occasional organelle fragments and double membrane structures.     

In-vitro-studies on the influence of cations, neurotransmitters and tubocurarine on calcium-ganglioside-interactions.

The influence of K⁺, Na⁺, Mg⁺⁺, Li⁺, a serotonin, acetylcholine and tubocurarine on calcium-ganglioside-interactions was studied by way of equilibrium dialysis using ⁴⁵Ca as tracer. Experiments were carried out at 22 °C and 4 °C, respectively. The concentrations of the substances were in the range of physiologically relevant conditions. Cations caused a release of Ca⁺⁺ from calcium-ganglioside-complexes in the sequence of their molar efficiency: Mg⁺⁺ ≈ Li⁺ > K⁺ ≈ Na⁺. Tubocurarine, serotonin and acetylcholine also affected calcium-ganglioside-interactions. Ca⁺⁺ was displaced from ganglioside most effectively by tubocurarine, followed by serotonin, whereas acetylcholine competed considerably more weakly.     

Lithium on glucose uptake in brain; role of glucose-1,6-P2 as a regulator of hexokinase

When given intraperitoneally to mice, lithium chloride decreased α-glucose-1,6-P₂ in the brain to about 30% of normal. This may explain the observation that Li⁺ stimulates glucose utilization by brain and other tissues insofar as α-glucose-1,6-P₂ inhibits animal hexokinase strongly. Glucose-1,6-P₂ synthase activity of brain was much lower in Li⁺-animals when assayed without added divalent metal cofactor such as Mg²⁺ but the same with Mg²⁺ in the assay. This results because Li⁺ replaces the tightly bound activator, probably Zn²⁺. These results demonstrate the importance of α-glucose-1,6-P₂ in regulation of hexokinase and suggest that normal energy metabolism of the brain may readily become sensitive to control by metal ion concentration.     

Toward a Four‐Electron Redox Quinone Polymer for High Capacity Lithium Ion Storage

Despite recent advances, current polymeric organic cathode materials have failed to incorporate a high degree of lithium storage in a small molecular framework, resulting in low capacities relative to monomers. This report discloses the development of a lithium salt polymer of dihydroxyanthraquinone (LiDHAQS) capable of storing four Li⁺ per monomer. The combination of storing four Li⁺ per monomer and a low molecular weight monomer results in a capacity of 330 mA h g^?1, a record for this class of material. The additional redox events responsible for added Li⁺ storage occur between 3.0 and 3.6 V versus Li/Li⁺ resulting in an average discharge potential of 2.5 V versus Li/Li⁺. These metrics combined yield a high energy density of 825 W h kg^?1 which is a 55% improvement over commercial lithium cobalt oxide. The high performance of LiDHAQS makes it a promising material for next generation Li⁺ cathodes.     

Sodium Transport in Capillaries Isolated from Rat Brain

Abstract: Brain capillary endothelial cells form a bloodbrain barrier (BBB) that appears to play a role in fluid and ion homeostasis in brain. One important transport system that may be involved in this regulatory function is the Na⁺,K⁺-ATPase that was previously demonstrated to be present in isolated brain capillaries. The goal of the present study was to identify additional Na⁺ transport systems in brain capillaries that might contribute to BBB function. Microvessels were isolated from rat brains and ²²Na ⁺ uptake by and efflux from the cells were studied. Total ²²Na ⁺ uptake was increased and the rate of ²²Na ⁺ efflux was decreased by ouabain, confirming the presence of Na⁺,K⁺-ATPase in capillary cells. After inhibition of Na⁺,K⁺-ATPase activity, another saturable Na ⁺ transport mechanism became apparent. Capillary uptake of ²²Na ⁺ was stimulated by an elevated concentration of Na ⁺or H⁺ inside the cells and inhibited by extracellular Na⁺, H⁺, Li⁺, and NH₄⁺. Amiloride inhibited ²²Na ⁺ uptake with a K_i between 10^?5 and 10^?6M but there was no effect of 1 mM furosemide on ²²Na⁺ uptake by the isolated microvessels. These results indicate the presence in brain capillaries of a transport system capable of mediating Na ⁺/ Na ⁺ and Na ⁺/H ⁺ exchange. As a similar transport system does not appear to be present on the luminal membrane of the brain capillary endothelial cell, it is proposed that Na ⁺/H ⁺ exchange occurs primarily across the antiluminal membrane.     

Lithium treatment of affective disorders: effects of lithium on the inositol phospholipid and cyclic AMP signalling pathways

The effects of lithium (Li⁺) on the adenylyl cyclase and inositol phospholipid receptor signalling pathways were compared directly in noradrenergic and carbachol stimulated rat brain cortical tissue slices. Li⁺ was a comparatively weak inhibitor of noradrenaline-stimulated cyclic AMP accumulation with an IC₅₀ of approx. 20 mM. By contrast, half-maximal effects of Li⁺ on inositol monophosphate (InsP) accumulation in [³H]inositol labelled tissue slices occurred at about 1 mM. A similar IC₅₀ for Li⁺ of about 1 mM was also obtained for noradrenaline-stimulated accumulation of CMP-phosphatidate (CMPPA), a sensitive indicator of intracellular inositol depletion, in tissue slices that had been prelabelled with [³H]cytidine. The effect of myo-inositol (inositol) depletion on the prolonged activity of phosphoinositidase C (PIC) was examined in carbachol-stimulated corticol slices using a novel mass assay fro InsP. Exposure to a maximal dose of carbachol for 30 min in the presence of 5 mM Li⁺ caused a 10-fold increase in the level of radioactivity associated with the InsP fraction, but only a 2-fold increase in InsP mass. During prolonged incubations in the presence of both carbachol and Li⁺ the accumulation of InsP mass was enhanced if 30 mM inositol was included in the medium. The results are comptable with the inositol depletion hypothesis of Li⁺ action but do not support the concept that adenylyl cyclase or guanine nucleotide dependent proteins represent therapeutically relevant targets of this drug.     

Lithium induced changes in intracellular free magnesium concentration in isolated rat ventricular myocytes

We have examined the effect of exposing isolated rat ventricular myocytes to lithium while measuring cytosolic free magnesium ([Mg²⁺]_i) and calcium ([Ca²⁺]_i) levels with the fluorescent, ion sensitive probes mag-fura-2 and fura-2. There was a significant rise in [Mg²⁺]_i after a 5 min exposure to a solution in which 50% of the sodium had been replaced by Li⁺, but not when the sodium had been replaced by bis-dimethylammonium (BDA). However, there were significant increases in [Ca²⁺]_i when either Na⁺ substitute was used. The possibility that Li⁺, which enters the cells, interferes with the signal from mag-fura-2 was eliminated as Li⁺ concentrations up to 10 mM had no effect on the dye's fluorescence signal. A possible explanation for these findings is that Li⁺ displaces Mg²⁺ from intracellular binding sites. Having considered the binding constants for Mg²⁺ and Li⁺ to ATP, we conclude that Li⁺ can displace Mg²⁺ from Mg-ATP, thus causing a rise in [Mg²⁺]_i. This work has implications for other studies where Li⁺ is used as a Na⁺ substitute.     

Effects of systematically administered lithium on tryptophan transport and exchange in plasma-membrane vesicles isolated from rat brain

The effect of lithium on the sodium-dependent high-affinity system for tryptophan uptake was examined in plasma membrane vesicles derived from rat brain. We demonstrated that Na⁺ could be replaced by lithium in the external medium and the presence of lithium produced an increase in theV _max of the tryptophan transport whereas it had no significant effect on theK _m for the substrate. Plasma membrane vesicles derived from synaptosomes obtained from long-term lithium-treated rats are able to accumulate tryptophan to a greater extent than normal rats and maintain a more negative membrane potential than controls. Our data support the idea that the stimulation by lithium of the high-affinity uptake system for tryptophan by maintaining adequate membrane potentials across the membrane, could lead to the stabilization of serotonin production, as has been demonstrated in long termlithium treatment.     

Gene Expression Profiling of Peri-Implant Healing of PLGA-Li+ Implants Suggests an Activated Wnt Signaling Pathway In Vivo

Bone development and regeneration is associated with the Wnt signaling pathway that, according to literature, can be modulated by lithium ions (Li⁺). The aim of this study was to evaluate the gene expression profile during peri-implant healing of poly(lactic-co-glycolic acid) (PLGA) implants with incorporated Li⁺, while PLGA without Li⁺ was used as control, and a special attention was then paid to the Wnt signaling pathway. The implants were inserted in rat tibia for 7 or 28 days and the gene expression profile was investigated using a genome-wide microarray analysis. The results were verified by qPCR and immunohistochemistry. Histomorphometry was used to evaluate the possible effect of Li⁺ on bone regeneration. The microarray analysis revealed a large number of significantly differentially regulated genes over time within the two implant groups. The Wnt signaling pathway was significantly affected by Li⁺, with approximately 34% of all Wnt-related markers regulated over time, compared to 22% for non-Li⁺ containing (control; Ctrl) implants. Functional cluster analysis indicated skeletal system morphogenesis, cartilage development and condensation as related to Li⁺. The downstream Wnt target gene, FOSL1, and the extracellular protein-encoding gene, ASPN, were significantly upregulated by Li⁺ compared with Ctrl. The presence of β-catenin, FOSL1 and ASPN positive cells was confirmed around implants of both groups. Interestingly, a significantly reduced bone area was observed over time around both implant groups. The presence of periostin and calcitonin receptor-positive cells was observed at both time points. This study is to the best of the authors'' knowledge the first report evaluating the effect of a local release of Li⁺ from PLGA at the fracture site. The present study shows that during the current time frame and with the present dose of Li⁺ in PLGA implants, Li⁺ is not an enhancer of early bone growth, although it affects the Wnt signaling pathway.     

Na+ (Li+)-proline cotransport inEscherichia coli

Summary Na⁺ and Li⁺ were found to stimulate the transport ofl-proline by cells ofEscherichia coli induced for proline utilization. The gene product of the put P gene is involved in the expression of this transport activity since the put P⁺ strains CSH 4 and WG 148 show activity and the put P^– strain RM 2 fails to show this cation coupled transport. The addition of proline was found to stimulate the uptake of Li⁺ and of Na⁺. Attempts to demonstrate proline stimulated H⁺ uptake were unsuccessful. It is concluded that the proline carrier (coded by the put P gene) is responsible for Na⁺ (or Li⁺)-proline cotransport.     

LITHIUM INHIBITS GROWTH IN A MURINE NEURAL PRECURSOR CELL LINE

The influence of lithium on cell growth and cell viability was studied in short-term cultures of a neural precursor cell line (NT) developed from a murine teratocarcinoma. At very low concentrations ranging from 0.1 m to 1 m Li₂CO₃(equivalent to therapeutic blood concentrations) there was no difference between untreated and treated cultures. 10 m lithium (Li⁺) was found to be toxic with 33% of cell death, while there was inhibition of growth without cell death at concentrations of 2.5 m and 5 m of Li⁺. In experiments where 2.5 m Li⁺was added at the time of seeding, there was growth arrest on day 1 followed by recovery on day 2. Flow cytometric analysis revealed that cells treated with Li⁺were blocked in S phase. At 5 m concentration of Li⁺, the recovery occurred on day 3 and the plating efficiency was significantly low. The ability to form colonies in soft agar was reduced at 2.5 m and 5 m concentrations of Li⁺to an equal extent. Thus, Li⁺has growth inhibitory as well as anchorage-independent growth reducing effects. The NT cell line therefore would be a good model system to study the mechanism of teratogenic effect of Li⁺.     

Lithium-selective permeation through lipid bilayer membranes mediated by a di-imide ionophore with nonsymmetrical imide substituents (ETH1810)

Summary The neutral, noncyclic Li^–-selective ionophore ETH1810, which is a di-imide, differs structurally from previous similar ionophores by removal of the intramolecular symmetry of the N-imide substituents. Properties of this ionophore, as a potential carrier of lithium, were probed through studies of ionophore-induced changes in electrical properties of lipid bilayer membranes. ETH1810 was found capable of transporting lithium and other monovalent cations, across lipid bilayer membranes, forming 21 ionophore: ion membrane-permeating species. It was found to be 10-fold more potent than ETH1644, which was the previous best ionophore of this type. The selectivity sequence among alkali cations was found to be: Li⁺(1)>Na⁺ (0,009)>K⁺ (0.004)>Cs⁺(0.0035). Among the physiological alkali cations, it constitutes a 40 (vs. Na⁺) to 160% (vs. K⁺) improvement over ETH1644. ETH1810 was also found to be capable of acting as a carrier of biogenic amines and related molecules, with the following selectivity sequence: tryptamine (20)>phenylethylamine (7.8)>tyramine (4.3)>serotonin (2.5)>Li⁺ (1)>NH ₄ ⁺ (0.013)>dopamine (0.012). It was found that protons, at physiological concentrations, do not interfere with the lithium transport mediated by ETH1810. The relationship between the improvements in ionic selectivity and potencyvs. the differences in structural features is discussed.     

THE UPTAKE OF LOW CONCENTRATIONS OF LITHIUM IONS INTO RAT CEREBRAL CORTEX SLICES AND ITS DEPENDENCE ON CATIONS

—Rat cerebral slices were incubated in oxygenated Krebs-Ringer bicarbonate glucose saline, and the uptake of Li⁺ was measured after periods of 15 s to 5 min. Saturation was not seen within the concentrations of Li⁺ employed (0·5-2·0 mm ). The half-time of the uptake was 7·9 min. At steady state, after 1 h incubation, the concentration of Li⁺ in the tissue was linearly related to that of the medium (0·5-1·5 mm Li⁺) with a concentration ratio of 1·29–1·66. The concentrations of K⁺ and Na⁺ in the slices incubated without Li⁺ were found to be (μmol/g incubated wt, mean ±s.d .) 63·8 ± 9·6 and 96·2 ± 7·8 respectively (n = 28). In the presence of media with 1·5 mm -Li⁺, the K⁺ and Na⁺ in the slices were 56·2 ± 8·8 and 101·0 ± 7·7 respectively (n = 37). The concentration of Li⁺ in the slices, after 1 h incubation, increased in a non linear way as the concentration of K⁺ in the medium was decreased within a range of 0·10 mm -K⁺. In the absence of K⁺ in the medium the uptake of Li⁺ was approx 50% higher than in the presence of 4·9 mm -K⁺. There was an inverse linear relationship between the concentration of Li⁺ in the slices and that of Ca²⁺ in the medium within the range of 0-5·2 mm (-0·13 mm -Li⁺/mm Ca²⁺). The concentration of Li⁺ in the slices increased by approx 10% when the Mg²⁺ in the medium was increased from 1·3 mm to 2·6 mm . Changes of the concentration of Na⁺ between 120 mm and 170 mm in the medium had no significant effect on the Li⁺ uptake.     

Effect of potassium and lithium ions on protein synthesis in the sea urchin embryo

The effects of K⁺ and Li⁺, alone and in combination, on protein synthesis were determined in two species of sea urchin, from fertilization through gastrulation. Embryos treated with Li⁺ show a decline in rates of [¹⁴C]valine uptake and incorporation beginning after cleavage. Li⁺-induced cecline in protein synthesis is reversed by co-exposure to increasing concentrations of K⁺. K⁺ alone is without effect on protein synthesis. K⁺ is effective in counteracting the effects of Li⁺ only if both ions are present concurrently. The data presented supports the hypothesis that K⁺ permits normal morphological development in the presence of Li⁺ by competitively blocking the effects of Li⁺ at the subcellular level.     

Lithium-Induced respecification of pattern in Paramecium

The long-known teratogenic effects (dorsalisation) of lithium on amphibian embryos has recently raised renewed interest. As it is known that lithium blocks the polyphosphoinositide (PI) cycle, causing a depressed level of myo-inositol, and as injections of myo-inostiol have been shown to rescue the effects of Li⁺, it was postulated that Li⁺ causes a flattening of gradients of PI cycle activity underlying the developmental polarities. We have studied the effect of Li⁺ on the morphogenesis of the unicellular organism, Paramecium. We show (1) that exposure to 25 mM Li⁺ during division yields precise distorsions of the cortical pattern that can be explained by a uniformisation of surface growth i.e. partial suppression of the right/left and antero/posterior asymmetries and (2) that Li⁺ effects are rescued by injection of myo- inositol. These results suggest that spatially graded activity of the PI cycle (ensuring in turn a spatially graded distribution of secondary messengers directly involved in the morphogenetic processes) appeared early in evolution. © 1992 Wiley-Liss, Inc.